2 alpha-methyl-9 alpha-bromo-17 alpha-hydroxy-4-pregnene-3, 11, 20-trione 17-acylates



United. States Patent 2,992,245 Za-METHYL-9a-BROMO-'17a-HYDROXY-4-PREG- NEN E-3,1-1,20-TRIONE 17-A'CYLATES John A. Hogg, Charleston Township, Kalamazoo County,

Frank H. Lincoln, Kalamazoo, and'William P. Schneider, Kalamazoo Township, Kalamazoo County, MliClL, assignors to The Upjohn Company, Kalamazoo, Mich.,

a corporation of Delaware No Drawing. Filed Dec. '14, 1959, Ser. No. 859,098

2 Claims. (Cl. 260397.45)

I This invention relates to novel steroid esters and more particularly to 2a-methyl-9m-brorno-17ot-hydroxy-4-pregnone-3,11,20-trione 17-acylates and toa process for the production thereof.

The novel 2a-methyl-9u-bromo-l7a-hydroxy-4-pregnene-3,11,20-tn'one 17-acylates of this invention are highly active oral progestational agents and are moreover useful in the inhibition of ovulation. An advantage of the compounds of this invention is their low mineralocorticoid activity. 7

The novel compounds of this invention can be prepared and administered to birds and mammals (including a Grams 2m-methyl-9u-bromo- 17 a-hydroxy-4-pregnene-3, 1 1,

20-trione 17-acetate Lactose USP The finely powdered steroid and lactose are mixed well and granulated with syrup-starch paste. Starch and calcium stearate are used as lubricants in the compressing step.

The oral administration of 1 tablet daily is useful in the treatment of secondary amenorrhea in humans. The process of this invention comprises dehydration of 2a-methyl-1l 3,17adihydroxy 4 pregnene-3,20-dione to obtain 2ot-methyl- 1 7a-hydroXy-4,9 l l )-pregnadiene-3,20- dione; acylating the latter compound with an acylating agent to obtain the corresponding 2a-methyl-l7a-hydroxy- 4,9(11)-pregnadiene-3,20-dione l7-acylate; treating the 1 7-acylate thus produced with a source of hypobromous acid to obtain the corresponding 2a-tmethyl-9a-bromo- 115,17a-dihydroxy-4-pregnene-3,20-dione 17-acylate and oxidizing the latter compound to obtain the corresponding 2a-methyl-9a-bromo-17a-hydroxy-4-pregnene-3J1,20- trione 17-acylate.

- The novel compounds of this invention and the process for their preparation are illustratively represented by the following reaction scheme:

CH: CH:

(EH: (EH O=O OHa C= on ---0H 0.. l

CH CH5" CH: CH5

CH: CH

"-OAc "-OAc HO Br 1 CH3,"

CH8" CH3" =0 -"OAc v of B! CH2 CH I wherein Ac is the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive.

The starting material for this invention is prepared in accordance with the preparations and examples of US. Patent 2,865,935, particularly Example 5, to give 2amethyl-l 15,17m-dihydroxy-4-pregnene-3,20-dione.

In carrying out the process of this invention, Zea-methyll1,9,l7a-dihydroxy-4-pregnene-3,ZO-dione is dehydrated to 20 methyl-17u-hydroXy-4,9(11)-pregnadiene-3,20-dione by methods known in the art, e.g., by a dehydrating agent such as phosphorous oxychloride, thionyl chloride, hydrochloric acid or sulfuric acid and acetic acid or by pyrolysis as shown in US. Patents 2,640,838 and 2,640,839, or the dehydration can be effected by the preferred method of reacting 2a methyl-11,8,17a-dihydroxy-4-pregnene-3,20- dione with a carboxylic acid N-haloamide or N-haloimide, according to the procedure of US. Patent 2,838,498, e.g., N-bromoacetarnide in pyridine followed by anhydrous sulfur dioxide.

The Za-methyI-I 7ot-hydroxy-4,9 l 1 )-pregnadiene-3,20- dione thus produced, is then acylated at the 17-position to produce the corresponding Zea-methyl-17u-hydroxy-4,9

(11)-pregnadiene-3,20- dione 17-acylate according to procedures well known in the art for esterifying tertiary, hydroxy groups, e.g., Babcock et al., I. Am. Chem. Soc. 80, 2904 (1958), Huang-Minlon et al., I. Am. Chem. Soc. 74, 5394 (1952) and by refluxing in acetic anhydride in the presence of calcium carbonate. Preferably the esterification is accomplished using the acid anhydride of an aliphatic acid, e.g., acetic, propionic, butyric, valeric, hexanoic, lauric, trimethylacetic, isobutyric, isovaleric, tertiary butylacetic or formic acid (in the presence of acetic anhydride), a cycloaliphatic acid, e.g., fi-cyclopentylpropionic, cyclohexane-carboxylic, cyclohexylacetic, an alkaryl acid, e.g., benzoic, phenylacetic, ,B-phenylacetic, B phenylpropionic, m-, p-toluic, a saturated dibasic acid (which can be converted into water soluble, e.g., sodium salts), e. g., succinic, adipic, a monobasic unsaturated acid, e.g., acrylic, crotonic, undecylenic, propiolic, Z-butynoic, undecolic, cinnamic, dibasic unsaturated acids (which can be converted into water soluble, e.g., sodium salts), e.g., maleic and citraconic, and the like in the presence of an acid catalyst, e.g., p-toluenesulfonic acid.

The selected 2a-methyl-17a-hydroxy-4,9 1 1)-pregnadiene-3,20-dione l7-acylate thus obtained is converted to the corresponding Zea-methyl 9a bromo-11/3,17ot-dihydroxy 4 pregnene-3,20-dione 17 acylate by methods known in the art, e.g., using N-bromoacetamide in the presence of perchloric acid according to the procedure of U.S. Patent 2,852,511.

The selected 2a-methyl-9a-bromod1fl,17u-dihydroxy- V 4-pregnene-3,20adione l7-acylate thus obtained is then oxidized by known methods, e.g., chromic acid in acetic acid, to give the respective 2a-methyl-9u-bromo-17a-hydroxy-4-pregnene-3,11,20-t1ione 17 -acylate.

The following examples are illustrative of the process and products of this invention.

EXAMPLE 1 2a-methyl-1 7 a-hydroxy-4,9(1 1 -pregnadiene-3,20-di0ne A solution containing 3.60 g. of 2a-methyl-115,17udihydroxy-4apregnene-3,20-dione in ml. of pyridine at 25 C. was treated with 2.21 g. of: N-bromoacetamide. After 20 minutes the solution was cooled and an excess of anhydrous sulfur dioxide was added with stirring. The reaction mixture was kept at about 25 C. for a period of 30 minutes and then cooled. 100 ml. of water was then added with stirring to the cooled reaction mixture and the cooling was continued for several hours keeping the temperature at 5 C. The precipitate thus obtained was collected on a filter, washed with Water and dried under vacuum at 70 C. to give 2.9 g. of Zoe-methyl- 17 m-hydroxy-4,9 1 1 -pregnadiene-3 ,20-dione. The crude product thus obtained was dissolved in a mixture of 50 ml. of methylene chloride and 25 ml. of Skellysolve B hexanes and chromatographed on a column containing 150 g. of Florisil synthetic magnesium silicate. The column was eluted with 160 ml. fractions of 8% acetone in Skellysolve B hexanes. Fractions 3-13 were combined to give 1.52 g. of product, which on recrystallization from acetone: Skellysolve B hexanes gave 0.93 g. of Zea-methyl- .l7a-hydroxy-4,9 1 1)-pregnadiene-3 ,20-dione melting at 229-231 C., [od +92 (chloroform).

Analysis-Gabi for C H O C, 77.15; Found: C, 77.85; H, 8.79.

EXAMPLE 2 Za-methyI-I 7u-hydroxy-4,9 (11 )-pregnadiene-3 ,20-dione 1 7 -acetate poured into 96 m1. -of-water. The aqueous mixture was 4 chilled at 5 C. until a precipitate was obtained. The p pit t was col ctedon afil e a Washed w thhold water. The precipitate was then dissolved in 15 ml. of methylene chloride, washed with water, dried over sodium sulfate, and concentrated to about 5 ml. Methanol (10 ml.) was then added and the solution was concentrated to 9 ml. The concentrated solution was then treated with 0.15 ml. of 10% aqueous sodium hydroxide solution. After cooling, the formed crystals were collected on a filter to give 0.71 g. of Zea-methyl-l7a-hydroxy-4,9=(11)- pregnadiene-3,20-dione 17-acetate melting at 24l-243C. Recrystallization from methanol gave 0.65 g. of Zea-methyl-17u-hydroxy-4,9(1l)-pregnadiene 3,20-dione 17-acetate melting at 241-243 C., [041 +75 (chloroform);

1313? 1727, 1675, 1640, and 1618 cm.-

ln the same manner substituting the anhydride of another hydrocarbon earboxylic acid, e.g., those acids previously listed, for acetic anhydride in the procedure of Example 2 is productive of the corresponding Zea-methyll7oc-hYdlGXY-4,9( 11 )-pregnadiene-3,20-dione 17 -acylate,

17-phenylacetate and the like.

EXAMPLE 3 2a-methyl-9a-br0mo-1 15,1 7u-dihydroxy-4-pregnene- 3,20-dione 1 7-acetate To ga olutionof 4.40 g. of Za-methyl-Ua-hydroxy- 4,9(11)-pregnadiene-3,20=dione 17-acetate in 250 ml. of t-butyl alcohol and 50 ml. of methylene chloride was addeda solution of 12.5 ml. of 70% perchloric acid in 87 ml. of water followed by a solution or 1.88 g. of N- bromoacetamide in 50 ml. of t-butyl alcohol. After stirring the reaction mixture for a period of about 15 minutes, a solution of 2.5 g. of sodium sulfite in 40 ml. of water was added and the reaction mixture was carefully concentrated to about 440 ml. under reduced pressure with no external heat. The concentrate was stirred and 500 ml. of water was added to give 5.80 g. of 2amethyl-9u-bromo 11p,17u-dihydroxy-4-pregnene 3,20- dione 17-acetate as a yellow crystalline solid melting at 168-170 C. An analytical sample was prepared by recrystallizing'Ofi g. of the yellow crystalline solid from a mixture of methylene chloride and Skellysolve B hexanes to 'give0.4 g. of 2a-methyl-9a-bromo-11B,l7a=dihydroxy- 4-pregnene-3,20-dione l7-acetate melting at 170-l72 C. with decomposition.

Analysis.-Ca1cd. for C24H33BIO5: Br, 16.60.

In the same manner substituting another 2a-methyl- 17 a-hydroxy-4,9 1 1)-pregnadiene-3 ,20-dione 17,-acylate wherein the acyl radical is that of an acid previously listed, for 2ot-methyl-17a-hydroxy-4,9 1 1)-pregnadiene- 3,20-dione 17-acetate in the procedure of Example 3 is productive of the corresponding 2a-methyl-9u-brorno- 11B,17a-dihydroxy-4-pregnene-3,ZO-dione 17-acetate, e.g.,

Br, 16.60. Found:

2a-m611hY1-9a-b10m0-11fl, 17 a-dihydroxy-4-pregnene-3.20-

dione l7-propionate,

2a-methyl-9a-bromo-11fi, 17 u-dihydroxy-4-rpregnene-3,20-

dione 17-butyrate,

2a-methyl-9a-bromo-llfi, 17a-dihydroxy-4-pregnene-3,20-

dione 17-eaproate,

2a-methyl-9a-bromo-11B, l7a-dihydroxy-4-rpregnene-3,20-

dione 17- p-cyclopentylpropionate) 2a-methyl-9a-br0m0-11B, 17a-dihydroxy-4apregnene-3,20-

dione 17-phenylacetate and the like.

EXAMPLE 4 2a-methyl-9a-br0m0-1 7a-hydroxy-4-pregnene- 3,11,20-trione 17-acetate To a stirred mixture of 4.2 g. of 2a-methyl-9a-bromo- 115,17a-dihydroxy-4-pregnene-3,20-dione 17-acetate in 100 ml. of acetic acid was added a solution of 4.2 g. of sodium dichromate in 25 ml. of acetic acid. After about 17 hours the reaction mixture was cooled to 15 C. and 400 ml. of water was added to precipitate the product. The precipitate was collected on a filter, washed with water and dried to give 3.01 g. of 2a-methyl-9ixbromo-17a-hydroxy-4-pregnene-3,11,20-trione 17-acetate melting at 167170 C. with decomposition. A 2.6 g. portion of the product thus obtained was dissolved in 50 ml. of methylene chloride and 50 ml. of Skellysolve B hexanes and poured onto a chromatographic column containing 125 g. of Florisil synthetic magnesium silicate. The product was eluted with 4.5 liters of acetone: Skellysolve B hexanes 7:93 taking 150 ml. fractions. After evaporating the solvent, fractions l227, weighing 2.36 g., were combined and crystallized from methylene chloride-Skellysolve B hexanes to give 2.03 g. of Zea-methyl- 9oz bromo 17a hydroxy 4 pregnene 3,11,20 trione 17-acetate melting at 167-170 C. with decomposition, [a] +197 (chloroform).

Analysis.Calcd. for C H BrO C, 60.12; H, 6.52; Br, 16.67. Found: C, 60.32; H, 6.81; Br, 17.00.

In the same manner substituting another 2a-methyl-9abromo 115,170; dihydroxy 4 pregnene 3,20 dione 17-acy1ate, wherein the acyl radical is that of an acid previously listed, for 2a-methyl-9a-bromo-11p,17a-dihydroxy-4-pregnene-3,ZO-dione 17-acetate in the procedure of Example 4 is productive of the corresponding Za-methyl-9u bromo 17a hydroxy 4 pregnene 3,11,20-t1ione 17-acylate, e.g., 2u-methyl-9u-bromo-l7u-hydroxy-4- pregnene-3,11,2 0-trione 17-propionate, 2u-methyl-9ot-bromo 17oz hydroxy 4 pregnene 3,11,20 trione 17- butyrate, 2a methyl 9oz bromo 17a hydroxy 4- pregnene 3,11,20 trione 17 caproate, 2a methylc bromo 17a hydroxy 4 pregnene 3,11,20 trione 17 (,B cyclopentylpropionate), 2oz methyl 90:- bromo 17a hydroxy 4 pregnene 3,11,20 trione 17-pheny1acetate and the like.

We claim:

1. 2a methyl 90c bromo a hydroxy 4 pregnene-3,11,20-trione 17-acylate, wherein the acyl radical is that of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive.

2. 2oz methyl 9a bromo 17m hydroxy 4 pregnene-3, 1 1,20-trione 17-acetate.

References Cited in the file of this patent UNITED STATES PATENTS 2,835,680 Fried May 20, 1958 2,838,498 Magerlein et al. June 10, 1958 2,852,511 Fried Sept. 16, 1958 2,865,935 Schneider et a1 Dec. 23, 1958 2,892,851 Bergstrom et a1 June 30, 1959 OTHER REFERENCES Bergstrom et al.: J.A.C.S., volume 81, pp. 4432-33 (August 1959).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2,992 245 July 11 1961 John A, Hogg et a1,

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent. should read as corrected below.

Column 4 line 14 for '?24l-=243 Cr" read 2411-.2441 C. line 66 for "17=acetate" read 17=-acy1ate Signed and sealed this 28th day of November 1961 (SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Attesting Officer I Commissioner of Patents USCOMM-DC' 

1. 2A - METHYL - 9A - BROMO - 17A - HYDROXY - 4 - PREGNENE-3,11,20-TRIONE 17-ACYLATE, WHEREIN THE ACYL RADICAL IS THAT OF A HYDROCARBON CARBOXYLIC ACID CONTAINING FROM 1 TO 12 CARBON ATOMS, INCLUSIVE. 